Nuclear mitochondrial DNA transfer revisited: From genomic noise to hallmark of aging.

Nuclear insertions of mitochondrial DNA (mtDNA) segments (NUMTs) represent an evolutionarily conserved phenomenon originating from the ancient endosymbiotic relationship between mitochondria and host cells. These insertions predominantly localize near intergenic or regulatory regions and are often enriched in tissues with high metabolic activity. Once regarded as inert pseudogenes or genomic artifacts, NUMTs are now recognized as dynamic elements capable of modulating nuclear architecture and cellular function. Advances in whole-genome sequencing have revealed a remarkable diversity of NUMTs across species, including polymorphic variants in humans that suggest ongoing NUMTogenesis. Stress-induced mitochondrial damage promotes mtDNA release and subsequent nuclear integration via non-homologous end joining, a mechanism that may be exacerbated in aging tissues. Studies suggest that NUMTs may intersect with some biological hallmarks of aging. Recently, NUMT accumulation in the brain was shown to correlate with cognitive decline and reduced lifespan, implicating NUMTs in biological aging and associated conditions. Additionally, NUMTs have been observed in oncogenic loci, suggesting potential roles in carcinogenesis. This review synthesizes current evidence on the molecular mechanisms underpinning NUMT generation and explores their intersection with aging biology. We examine how NUMTs may influence mitochondrial-nuclear communication, promote inflammation, and affect telomere dynamics and cellular senescence. We also highlight the relevance of understanding the biological impact of NUMTs across life stages and disease states to inform novel biomarkers and therapeutic strategies.

• Publication year

  2025

• Venue

  Ageing Research Reviews

• Publication date

  2025-09-03

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.arr.2025.102892PMID 40912404
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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